Effects of nicotine form and tobacco flavor on pharmacokinetics, subjective effects, and behavioral indicators of abuse liability of e-cigarettes.

Abstract

Introduction: Most contemporary e-cigarettes contain high concentrations of salt-based nicotine, which reduces respiratory irritation typically associated with free-base nicotine liquids. Flavorings can also be used in e-cigarettes to increase nicotine delivery and product appeal. The cumulative effects of nicotine form and flavor on abuse liability are unknown.

Methods: We conducted a double-blind within-subject, clinical trial (clinicaltrials.gov ID:NCT04231539). Using a standardized puffing protocol, regular users of e-cigarettes tested four liquid formulations (order randomized) of the same nicotine concentration (25.5 ± 2.4 mg/mL, 157.4 ± 14.5 mM): (1) unflavored with free-base nicotine; (2) tobacco-flavored with free-base nicotine; (3) unflavored with salt-based nicotine; (4) tobacco-flavored with salt-based nicotine. Endpoints, analyzed via linear mixed-effects modeling and ANOVA, included pharmacokinetic measures (area under the concentration-time curve, maximum concentration, time to maximum concentration), subjective drug effects (eg, liking, withdrawal relief, sensory effects), and behavioral economic demand (intensity, elasticity).

Results: Salt-based formulations produced higher maximum concentration values (P = .028), were rated as less harsh (P < .001), and created a more intense cooling sensation (P = .002) compared to free-base formulations. Tobacco-flavored formulations also showed a significantly more intense cooling sensation (P = .013) and a greater feeling of nicotine effect (not significant, P = .055) than unflavored formulations. Nominal rankings of study measures, regardless of statistical significance, showed formulations with salt-based nicotine consistently outperformed those with free-base nicotine, regardless of liquid flavor.

Conclusions: Our findings suggest that abuse liability of e-cigarettes is driven more by nicotine form than flavor among regular users. Future studies should consider the effect of nicotine form in conjunction with liquid flavor in other populations, including cigarette smokers seeking to quit.

Implications: Our study shows that, regardless of flavor, salt-based nicotine delivers more nicotine to users and is subjectively rated more favorably among participants compared to free-base nicotine, indicating a possibly higher abuse liability. These findings are key points that should be addressed in future studies aimed at examining the influence of nicotine form and liquid flavor in other populations, particularly those seeking to quit smoking cigarettes.